Project Summary/Abstract Several conditions with increased cardiovascular risk, such as obesity, hypertension and congestive heart failure, are characterized by both an increase in sympathetic activity and impairment of nitric oxide (NO) function. NO is known to modulate sympathetic activity, but less is know about the potential role of sympathetic activity on nitric oxide function. Recent data from our laboratory and the literature suggest a negative interaction between sympathetic activity and NO function, whereby conditions associated with sympathetic activation are accompanied by NO dysfunction. We propose that this interaction is particularly important in obesity associated hypertension. We hypothesized that the sympathetic activation characteristic of obesity-associated hypertension, contributes to the impairment in NO function reported in this condition. In Specific Aim 1 we propose to test the hypothesis that acute autonomic withdrawal will improve NO function in resistance vessels. We have previously shown that administration of the ganglionic blocker trimethaphan can be safely used in humans to induce transient and complete autonomic withdrawal. We and other have previously shown that obese individuals have an impaired response to NO-mediated dilation using the forearm circulation as a model. We propose to determine if this impaired NO- mediated dilation can be restored with acute autonomic withdrawal with trimethaphan. Our preliminary studies also suggest that sympathetic activation can contribute to other abnormalities observed in obesity. Thus, in Specific Aim 2 we propose to extend these studies by inhibiting central sympathetic outflow chronically, and determine the effects of this intervention on NO-mediated dilation, insulin resistance, and on biomarkers of inflammation and oxidative stress. PUBLIC HEALTH RELEVANCE: The findings of the present proposal will serve to improve our understanding of the mechanisms involved in obesity-associated hypertension with the ultimate goal of improving the treatment of this condition. If our hypothesis is true, our results will indicate that the sympathetic nervous system should be targeted in the treatment of obesity hypertension. (End of Abstract)